to be elevated, in the normal male adolescent range. Karyotyping is then performed revealing a 46,XY karyotype.

Given these ndings, a diagnosis of complete androgen insensitivity syndrome is made. A subsequent MRI reveals intrabdominal testes. The patient and her family are referred to adolescent gynecology and for psychological counseling. After a thorough discussion with her gynecologist, the determination is made to wait until breast development is complete and then plan for laparoscopic gonadectomy (removal of the testes) and subsequent hormone replacement with estrogen. The patient is also given a set of vaginal dilators and instructed on proper use.

Discussion

Primary amenorrhea is de ned by the absence of menarche by age 13 without secondary sexual characteristics or by age 15 with secondary sexual characteristics. Etiologies of primary amenorrhea can be characterized as gonadal dysgenesis, hypothalamic or pituitary disorders, anovulation, outfow tract abnormalities, and physiologic. The most common causes of primary amenorrhea are chromosomal abnormalities leading to gonadal dysgenesis, which accounts for approximately half of all cases. It is important to remember that all causes of secondary amenorrhea can also present as primary amenorrhea.

Evaluation of primary amenorrhea includes:

•\ Complete physical exam including:

––Vital signs

––Height

––Weight

––BMI calculation

––Breast examination with Tanner staging

––Skin examination (evidence of hirsutism, acne, striae, axillary/pubic hair with Tanner staging)

––Thyroid exam

––Genital and pelvic exam with focus on clitoral size, pubic hair development, intactness of the hymen, vaginal length, and presence of a cervix, uterus, and ovaries

•\ Laboratory evaluation including:

––Urine or serum pregnancy test

––TSH

––Prolactin

––Estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH)

––Androgens

––17-OH Progesterone

––Karyotype

diagnosis of exclusion—in the absence of an obvious underlying cause, brain imaging (MRI) should be performed to rule out a central nervous system (CNS) lesion. Bone mineral density testing is also an important consideration, particularly in a patient with a history of more than 6 months of amenorrhea, severe nutritional de ciency, or stress fractures. Patients typically present with low-normal LH and FSH levels and low serum estradiol. Treatment is focused on correction of the underlying cause in order to restore normal function of the hypothalamic–pituitary–ovarian axis, and in turn, normal ovulation.

––Isolated GnRH de ciency, a rare cause of primary amenorrhea, is caused by failure or proper migration or development of GnRH neurons. Kallmann syndrome is due to failure of GnRH neuron migration and is associated with anosmia. Several genes have been implicated in GnRH de ciency and can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion. The majority of Kallmann syndrome cases are due to mutations in the Kal1 gene and are inherited in an X-lined fashion. Patients present with low serum gonadotropin concentrations and low serum estradiol, and the clinical picture is dif cult to distinguish from constitutional delay of puberty. Treatment consists of induction of puberty followed by lifelong hormone replacement therapy with both estrogen and progesterone. Fertility can be readily achieved by administration of exogenous gonadotropins, preferably preparations of FSH and LH combinations.

––Hyperprolactinemia can cause amenorrhea by disrupting the pulsatile secretion of GnRH, leading to disruption of FSH and LH secretion. It is a common cause of secondary amenorrhea but can rarely be associated with primary amenorrhea, often accompanied by galactorrhea (milky breast discharge). Since prolactin can be increased after eating, a fasting level should always be drawn after an initial elevated value prior to initiating a full workup. Once the elevation is con rmed, a brain MRI should be performed. The most commonnding on MRI associated with amenorrhea is a prolactin secreting pituitary adenoma. Other non-structural causes of hyperprolactinemia are medication use (e.g., antipsychotics), hypothyroidism, and pregnancy. The management of hyperprolactemia is discussed in the chapter Hyperprolactinemia.

––Constitutional delay of puberty is characterized by both delayed adrenarche and gonadarche and is dif cult to distinguish from congenital GnRH de - ciency. It is ve times more common in boys than girls and as such should be considered a diagnosis of exclusion. Often, medical history will reveal a family history of delayed puberty. Patients will go on to have completely normal pubertal development at a later age [1–3].

•\ Gonadal Dysgenesis

Primary amenorrhea is most commonly caused by chromosomal or genetic abnormalities leading to gonadal dysgenesis. Given either partial or complete lack of ovarian function, patients will present with elevated FSH levels and low serum estradiol levels. Treatment consists of pubertal induction followed by lifelong hormone replacement therapy.

––Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome refers to congenital absence of the vaginal and uterus, although some females may exhibit variable degrees of uterine development. It is caused by either agenesis or hypoplasia of the Mullerian duct system. Clinical presentation is variable and depends on the degree of agenesis. Women with a normal, obstructed uterus and those with a rudimentary uterine horn with functional endometrium may present with cyclic pelvic pain and/or a painful pelvic mass. While there are some genetic mutations associated with MRKH, the majority of cases are sporadic. Imaging studies can help to clarify the nature of the agenesis (vaginal, cervical, uterine) and to differentiate it from imperforate hymen and transverse vaginal septum. Treatment consists of creation of a functional vagina, either through mechanical dilation or surgery as well as removal of an obstructed rudimentary horn. Given normal ovarian function, patients can undergo ovarian stimulation and oocyte retrieval and achieve pregnancy through embryo transfer into a gestational carrier.

For our patient, the diagnosis of complete androgen insensitivity syndrome (CAIS) is in the category of outfow tract obstruction. It is an X-linked recessive disorder in which 46,XY patients present with a female phenotype. It is due to a defect in the androgen receptor, which renders cells resistant to the action of testosterone. The testes are functional—testosterone is made in normal quantities by Leydig cells, but due to the receptor defect, it is unable to act on cells and patients fail to develop all testosterone-dependent male sexual characteristics. This process starts in utero. Failure of the androgen receptor to recognize testosterone action leads to regression of the Woll an ducts, while anti-Mullerian hormone (AMH), produced by Sertoli cells, leads to regression of the Mullerian ducts and its structures (the fallopian tubes, uterus, and upper third of the vagina). Given the dependence of testicular descent on testosterone action, the testes are typically located in the abdomen or inguinal region. At puberty, given the aromatization of testosterone to estrogen, normal breast development occurs. Axillary and pubic hair are scant given the lack of androgen action. The diagnosis is based upon the absence of the upper vagina, uterus, and fallopian tubes on physical exam and pelvic ultrasound, a male (46,XY) karyotype, and high serum testosterone concentrations (in the normal male range).

The differential diagnosis in a female presenting with primary amenorrhea, absent uterus, and a blind vaginal pouch includes Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. However, these women can be distinguished from those with CAIS by the presence of normal axillary and pubic hair, a 46,XX karyotype, and serum estrogen and testosterone concentrations in the normal female range. Partial androgen insensitivity syndrome is associated with less severe receptor defects than those seen in CAIS and can present with partial virilization and ambiguous genitalia (refer to chapter Ambiguous Genitalia).

Management of CAIS is focused on the creation of a functional vagina, psychological treatment for both the patient and her family, and reduction in the risk of malignancy by properly timed gonadectomy. Leaving the functional testes in place